1. Abstract Vaccine mismatch and delay continue to hamper seasonal influenza vaccination efforts. We propose here to develop EC-QIV, a novel quadrivalent influenza vaccine based on the immunologically dominant globular domain of hemagglutinin produced in an E.coli expression system (eHA1). The proof of concept for production of biologically active and correctly folded eHA1 has been demonstrated for the seasonal H1N1, H3N2, and two B lineage influenza viruses, as well as for several avian influenza viruses with pandemic potential. A key breakthrough of this technology is the successful production of the oligomeric form of eHA1. The eHA1 oligomer retains the receptor binding activity and the antigenicity of the parental HA molecule. The productivity of eHA1 is significantly higher than that of licensed vaccines. The low production cost of the E.coli system will allow EC-QIV to be highly competitive in the current saturated influenza vaccine market. A short production cycle will allow eHA1 to be more efficient in responding to emergence of drifted and or shifted influenza viruses. The eHA1 is focused on the immunodominant protective region of HA and has been shown to be more effective than the licensed influenza vaccines in protection against virus challenge in the ferret animal model. This unique technology has the potential to provide cheaper, faster, and more effective influenza vaccines. This Phase II SBIR proposal is centered on the development of a highly productive commercial manufacturing process that will provide significant surge capacity for prevention of seasonal and pandemic influenza.